The need to improve the solubility of active pharmaceutical ingredients (APIs) has been rising for decades. Today, this need is increasingly pressing, as the number of APIs that are poorly water-soluble (based on their BCS classification) is growing: while around 40% of APIs on the market show poor solubility, approximately 60% of new molecular entities (NMEs) have been reported to have solubility challenges, which represents a significant increase.[1] As a result, solubility-enhancing techniques have become an area of focus for pharmaceutical formulators. But why is the solubility of an API deemed so important in the pharmaceutical world? For an oral formulation, API solubility and permeability are critical factors for the absorption of the API in the gastrointestinal tract and its bioavailability at the site of action. However, the need for APIs with a good solubility or, where this is not the case, the need for ways to enhance solubility is not limited to oral formulations but is also a prerequisite for parenteral administration forms, as injectables or subcutaneous injection typically require the API to be present in a solubilized form. Different approaches to solubility enhancement are available (see Figure 1). Chemical approaches such as salt and prodrug formation are typically more feasible in early development stages, as they fundamentally alter the API’s chemical nature.

AIM This study aimed to fabricate, characterize and use maltose microneedles for transdermal delivery of doxorubicin. MATERIALS & METHODS Microneedles were fabricated by micromolding technique and evaluated for dimensions, mechanical properties and in situ dissolution. Microporation of human cadaver skin was confirmed by dye binding, histology, pore uniformity, confocal laser microscopy and skin integrity measurement. In vitro permeation studies were performed on vertical Franz diffusion cells. RESULTS Maltose microneedles were sharp, mechanically uniform and rapidly dissolvable. Microneedle insertion resulted in a marked decrease in lag time and a significant increase in the permeation across and into human skin (p < 0.05). The skin delivery profile was used to predict the steady-state plasma concentration. CONCLUSION Maltose microneedles are a promising physical technique to increase skin delivery.

Topical drug delivery systems provide localized drug action. A hydrophilic polymer such as polyvinyl alcohol is a multi-faceted excipient that can be used as a coating agent, lubricant, stability enhancer and viscosity-increasing agent. The objective of our study was to evaluate the use of polyvinyl alcohol polymer in preparing a topical gel with a diclofenac salt as the pharmaceutical active. The gel was characterized for its rheological and other properties and its effectiveness to deliver drug through dermatomed human skin compared to a similar commercially available topical gel. Topical polyvinyl alcohol based gel was prepared with propylene glycol, isopropyl alcohol, hydroxypropyl cellulose, and Transcutol (R) P. Formulation was tested for pH, rheology, adhesion, spreadability, skin irritation, in vitro drug distribution in skin, and permeation. The formulated topical gel delivered an average cumulative drug amount of 22.85 +/- 9.41 mu/cm2 across skin and delivered 10.30 +/- 9.09 mu/cm2 in the skin over 24 h. The mean cell viability value of 107.41 +/- 40.81% rendered by in vitro skin irritation test confirmed the formulated gel to be non-irritant to human skin. In conclusion, a safe efficacious and Theologically competent polyvinyl alcohol polymer based topical diclofenac gel was developed and characterized successfully. (C) 2017 Elsevier B.V. All rights reserved.

La presente invention concerne l'utilisation d'un sucre amine en tant que plastifiant dans des formulations comprenant un polymere en tant que support pour ingredients actifs, en particulier pour des compositions qui sont melangees intensivement par un traitement dans une extrusion a l'etat fondu, puis formulees par post-traitement approprie.

The KinetiSol® Dispersing (KSD) technology has enabled the investigation into the use of polyvinyl alcohol (PVAL) as a concentration enhancing polymer for amorphous solid dispersions. Our previous study revealed that the 88% hydrolyzed grade of PVAL was optimal for itraconazole (ITZ) amorphous compositions with regard to solid-state properties, non-sink dissolution performance, and bioavailability enhancement. The current study investigates the influence of molecular weight for the 88% hydrolyzed grades of PVAL on the properties of KSD processed ITZ:PVAL amorphous dispersions. Specifically, molecular weights in the processable range of 4 to 18 mPa · s were evaluated and the 4-88 grade provided the highest AUC dissolution profile. Amorphous dispersions at 10, 20, 30, 40, and 50% ITZ drug loads in PVAL 4-88 were also compared by dissolution performance. Analytical tools of diffusion-ordered spectroscopy and Fourier transform infrared spectroscopy were employed to understand the interaction between drug and polymer. Finally, results from a 30-month stability test of a 30% drug loaded ITZ:PVAL 4-88 composition shows that stable amorphous dispersions can be achieved. Thus, this newly enabled polymer carrier can be considered a viable option for pharmaceutical formulation development for solubility enhancement.

Objectives Mesoporous silicas (SLC) have demonstrated considerable potential to improve bioavailability of poorly soluble drugs by facilitating rapid dissolution and generating supersaturation. The addition of certain polymers can further enhance the dissolution of these formulations by preventing drug precipitation. This study uses fenofibrate as a model drug to investigate the performance of an SLC-based formulation, delivered with hydroxypropyl methylcellulose acetate succinate (HPMCAS) as a precipitation inhibitor, in pigs. The ability of biorelevant dissolution testing to predict the in vivo performance was also assessed. Key findings Fenofibrate-loaded mesoporous silica (FF-SLC), together with HPMCAS, displayed significant improvements in biorelevant dissolution tests relative to a reference formulation consisting of a physical mixture of crystalline fenofibrate with HPMCAS. In vivo assessment in fasted pigs demonstrated bioavailabilities of 86.69 ± 35.37% with combination of FF-SLC and HPMCAS in capsule form and 75.47 ± 14.58% as a suspension, compared to 19.92 ± 9.89% with the reference formulation. A positive correlation was identified between bioavailability and dissolution efficiency. Conclusions The substantial improvements in bioavailability of fenofibrate from the SLC-based formulations confirm the ability of this formulation strategy to overcome the dissolution and solubility limitations, further raising the prospects of a future commercially available SLC-based formulation.

Polyvinyl alcohol (PVAL) has not been investigated in a binary formulation as a concentration-enhancing polymer owing to its high melting point/high viscosity and poor organic solubility. Due to the unique attributes of the KinetiSol® dispersing (KSD) technology, PVAL has been enabled for this application and it is the aim of this paper to investigate various grades for improvement of the solubility and bioavailability of poorly water soluble active pharmaceutical ingredients. Solid amorphous dispersions were created with the model drug, itraconazole (ITZ), at a selected drug loading of 20%. Polymer grades were chosen with variation in molecular weight and degree of hydroxylation to determine the effects on performance. Differential scanning calorimetry, powder X-ray diffraction, polarized light microscopy, size exclusion chromatography, and dissolution testing were used to characterize the amorphous dispersions. An in vivo pharmacokinetic study in rats was also conducted to compare the selected formulation to current market formulations of ITZ. The 4-88 grade of PVAL was determined to be effective at enhancing solubility and bioavailability of itraconazole.

Polyvinyl alcohol has received little attention as a matrix polymer in amorphous solid dispersions (ASDs) due to its thermal and rheological limitations in extrusion processing and limited organic solubility in spray drying applications. Additionally, in extrusion processing, the high temperatures required to process often exclude thermally labile APIs. The purpose of this study was to evaluate the feasibility of processing polyvinyl alcohol amorphous solid dispersions utilizing the model compound ritonavir with KinetiSol® Dispersing (KSD) technology. The effects of KSD rotor speed and ejection temperature on the physicochemical properties of the processed material were evaluated. Powder X-ray diffraction and modulated differential scanning calorimetry were used to confirm amorphous conversion. Liquid chromatography–mass spectroscopy was used to characterize and identify degradation pathways of ritonavir during KSD processing and 13C nuclear magnetic resonance spectroscopy was used to investigate polymer stability. An optimal range of processing conditions was found that resulted in amorphous product and minimal to no drug and polymer degradation. Drug release of the ASD produced from the optimal processing conditions was evaluated using a non-sink, pH-shift dissolution test. The ability to process amorphous solid dispersions with polyvinyl alcohol as a matrix polymer will enable further investigations of the polymer’s performance in amorphous systems for poorly water-soluble compounds.

An epoxy derivatized monolithic silica capillary column (100 mu m i.d.) was used as a support for immobilization of penicillin G acylase (PGA), an enzyme used in the production of semisynthetic antibiotics. In order to allow for sensitive UV detection, the PGA-based monolithic capillary column was coupled to an open fused-silica capillary via a TFE (Teflon (R)) shrink tube sleeve (1 cm long, 300 mu m id.), which proved to be a robust, dead-volume free and easily replaceable connector. This configuration resulted in a duplex fritless column for capillary liquid chromatography (CLC) and electrically assisted CLC (eCLC). In particular, using the driving pressure (2-12 bar) supplied by the commercial CE instruments, CLC separations could be obtained in short time due to the low column backpressure of the monolith. In particular, the developed stationary phase characterized by the chiral recognition ability of PGA, was successfully applied in enantioseparation of arylpropionic acids of pharmaceutical interest (i.e., profens). As an example, by using a 7 cm long monolith capillary column, the enantioresolution (Rs > 3.0) of rac-ketoprofen was achieved in less than 2 min (pressure 12 bar) with a minimum plate height in the order of 20 mu m and using as a mobile phase a 50 mM phosphate buffer pH 7.0. Validation data such as repeatability of retention time (intraday <0.62, n = 6; interday < 1.62, n = 9; and column-to-column < 10.5, n = 2), linearity (r(2) = 0.999), and sensitivity (LOQ 0.25% (w/w) of (R)-ketoprofen with respect to (S)-ketoprofen) showed good method performance. The method was successfully applied to the determination of (S)-ketoprofen in pharmaceutical samples (tablets). (C) 2011 Elsevier B.V. All rights reserved.